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Enhancing blood flow and glucose uptake in insulin-resistant skeletal muscle


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Genders, Amanda Joan 2009 , 'Enhancing blood flow and glucose uptake in insulin-resistant skeletal muscle', PhD thesis, University of Tasmania.

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A key aspect of insulin action on muscle glucose uptake is capillary recruitment, and loss
of capillary recruitment is thought to contribute to muscle insulin resistance. Thus
enhancing insulin-mediated capillary recruitment may improve muscle insulin sensitivity.
Acute inhibition of the NO signalling pathway completely blocks capillary recruitment
and reduces glucose uptake by 50%. NO signals via cGMP which is hydrolyzed by
phosphodiesterases (PDEs). Site specific NO signalling can be enhanced by inhibiting
particular PDEs isoforms as shown by the use of Viagra® in treating erectile dysfunction.
PDE inhibition may therefore lead to an increase in capillary recruitment and glucose
uptake. Thus the aim of this project was to determine which PDE isoforms are expressed
in the muscle vasculature and whether inhibition of these PDEs could enhance glucose
uptake and capillary recruitment in normal and insulin resistant rats.
Skeletal muscle and aortic tissue were examined for PDE expression at both the mRNA
and protein level, and immunohistochemistry used to determine the distribution of PDE
expression in the vasculature. PDEs 1B, 5A, 9A, 10A and 11A were found to be
expressed in the skeletal muscle vasculature.
Zaprinast inhibits PDE isoforms 1, 5A, 9A, 10A and 11A and thus its effects were
examined during hyperinsulinaemic euglycaemic clamps in anesthetized rats. Zaprinast
moderately increased insulin's effect on glucose uptake and capillary recruitment. To
determine the effects of Zaprinast in a model of insulin resistance, a high fat fed (HFF)
model of insulin resistance was developed. High fat feeding abolished insulin mediated
capillary recruitment and significantly blunted insulin-mediated glucose uptake. In HFF
rats, Zaprinast was unable to enhance insulin's metabolic and vascular effects.
To further examine the defects in insulin sensitivity and NO signalling in HFF rats, an
alternative capillary recruitment agent, methacholine was administered locally into one
hindleg by retrograde infusion of the epigastric artery during hyperinsulinaemic
euglycaemic clamps. Methacholine was also unable to enhance insulin sensitivity in HFF
In conclusion, Zaprinast improved insulin-mediated capillary recruitment and glucose
uptake in normal rats. The heterogeneous vascular expression of PDE isoforms indicates
that an isoform specific PDE inhibitor may give a greater improvement in insulin
sensitivity, particularly in the HFF model where insulin's effects are already blunted.
However, the insensitivity of the HFF rats to methacholine and Zaprinast suggests that
increasing NO signaling via raised cGMP formation may be difficult due to factors such
as NO destruction in HFF rat vasculature.

Item Type: Thesis - PhD
Authors/Creators:Genders, Amanda Joan
Keywords: Insulin resistance, Musculoskeletal system, Muscles, Diabetes
Copyright Holders: The Author
Copyright Information:

Copyright 2009 the Author - The University is continuing to endeavour to trace the copyright
owner(s) and in the meantime this item has been reproduced here in good faith. We
would be pleased to hear from the copyright owner(s).

Additional Information:

Available for use in the Library and copying in accordance with the Copyright Act 1968, as amended. Thesis (PhD)--University of Tasmania, 2009. Includes bibliographical references

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